TY - JOUR
T1 - Time-dependent cognitive deficits associated with first and second generation antipsychotics
T2 - Cholinergic dysregulation as a potential mechanism
AU - Terry, Alvin V.
AU - Mahadik, Sahebarao P.
PY - 2007/3
Y1 - 2007/3
N2 - Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (α7) and muscarinic (M2) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D2 receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.
AB - Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (α7) and muscarinic (M2) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D2 receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.
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U2 - 10.1124/jpet.106.106047
DO - 10.1124/jpet.106.106047
M3 - Review article
C2 - 16966470
AN - SCOPUS:33847145927
SN - 0022-3565
VL - 320
SP - 961
EP - 968
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -